Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression changes with induction of in-vitro platinum-resistance in ovarian cancer cell lines.

ABSTRACT: We treated 8 human ovarian cancer cell lines with cisplatin in treatment/recovery cycles to induce in-vitro resistance to the drug. Microarrays measured gene expression at baseline and after each dose schedule (after recovery). OVCA cells lines (T8, OVCAR5, OV2008, IGROV1, C13, A2780S, A2780CP, and A2008) were used in the study. Cells were subject to sequential treatment with increasing doses of cis-diammine-dichloroplatinum (cisplatin, CIS), using three dosing schedules resulting in a total of 144 treatment/expansion cycles. Treatment schedules A, B and C included three treatments with 1, 2 and 3μg/ml CIS respectively, followed by three treatments with 3, 4 and 5μg/ml, respectively. Each CIS-treatment was followed by a cell recovery/expansion phase. Both CIS-resistance and genome-wide expression changes were measured serially in each cell line at baseline and after 3 and 6 CIS-treatment/expansion cycles. CIS-resistance was quantified using CellTiter-96, MTS proliferation assays (Fisher Scientific) and genome-wide expression was performed using Affymetrix Human U133 Plus 2.0 GeneChips as previously described.

ORGANISM(S): Homo sapiens

SUBMITTER: Steven Eschrich

PROVIDER: E-GEOD-23553 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

Marchion Douglas C DC Cottrill Hope M HM Xiong Yin Y Chen Ning N Bicaku Elona E Fulp William J WJ Bansal Nisha N Chon Hye Sook HS Stickles Xiaomang B XB Kamath Siddharth G SG Hakam Ardeshir A Li Lihua L Su Dan D Moreno Carolina C Judson Patricia L PL Berchuck Andrew A Wenham Robert M RM Apte Sachin M SM Gonzalez-Bosquet Jesus J Bloom Gregory C GC Eschrich Steven A SA Sebti Said S Chen Dung-Tsa DT Lancaster Johnathan M JM

Clinical cancer research : an official journal of the American Association for Cancer Research 20110817 19

<h4>Purpose</h4>Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.<h4>Experimental design</h4>Serial OV ...[more]

PMID: 21849418

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Project description:We investigated an acute kidney injury (AKI) model in rats induced by cisplatin (Cp) administration. The cisplatin is widely used since its biochemical and histopathological characteristics are representative of drug-induced AKI in humans. Male Wistar rats were dosed once ip with 0, 1 and 3 mg/kg cisplatin. Tubular necorsis was observed histopathologically in all treated rats and war recovery on day 26. Gene expression profiling of the kidney cortex with microarrays 3, 5, 8, and 26 days after single administration of 3mg/kg Cp revealed a major profile pattern characterized by maximally increased and decreased mRNA levels on day 8, with clear changes already found 3 days after treatment for about half of the mRNAs. The mRNA expression pattern after administration of 1mg/kg Cp was overall similar, yet with a dose-dependent smaller fold-change. In summary we found 274 mRNAs showing significantly altered levels in the kidney of which 162 were increased and 112 decreased, respectively. Functional interpretation of the proteins encoded by these mRNAs revealed induction of a DNA damage response likely caused by the known molecular activity of Cp as DNA alkylating agent. Increased mRNAs associated with apoptosis (encoded by the corresponding genes like B-cell lymphoma 3-encoded protein, Bcl3; mouse double minute 2 homolog, Mdm2; p21/WAF1 also known as cyclin-dependent kinase inhibitor 1), cell cycle regulation (encoded by the corresponding genes like Cyclin-G1, Ccng1; B-cell translocation gene 2, Btg2) and stress response may have partly been induced by the DNA damage, but also by the kidney damage associated with Cp administration. Increased levels of mRNAs indicating regeneration (encoded by the corresponding genes like SPARC- related modular calcium-binding protein 2, Smoc2; Tenascin C, Tnc) and decreased levels of mRNAs coding for proteins related to kidney function, indicating dedifferentiation, are likely related to the observed kidney injury. Male Han Wistar rats (8 weeks old) were randomly grouped (n = 6) and dosed once i.p. with 0, 1 or 3 mg/kg body weight cis-diamminedichloroplatinum (II) (cisplatin; Sigma Aldrich, Germany) diluted in 0.9% saline. For histopathological examination of the kidney and for kidney RNA isolation animals were euthanized on days 3, 5, 8 and 26.

Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used. In order to capture complex gene expression changes in the PBMCs derived from 15 CIS patients in comparison to 7 HCs, we performed a comprehensive study using Affymetrix Human Gene array U133 (HG-U133) with 45,000 probe sets representing approximately 33,000 human genes. The arrays were hybridized for 16 h at 45oC in a GeneChip® Hybridization Oven 640 (Affymetrix), washed and stained with R-phycoerythrin streptavidin in a GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning, and basic analysis. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis of microarrays was used. Differentially expressed genes were determined using a Welch two sample t-test. A p<0.05 was considered significant.

Dataset Information

Gene expression changes with induction of in-vitro platinum-resistance in ovarian cancer cell lines.

Publications

BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

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